Summary of work: The neuroanatomic and neurophysiologic underpinnings of age- associated cognitive and memory change remain unclear, as there is little information on longitudinal brain changes. We are performing annual magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA), aged 55 and older, to investigate the neurobiological basis of memory change. These evaluations will allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease. An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. In addition, we are using neuroimaging tools to investigate brain changes in response to estrogen and testosterone therapy in older women and men. These studies are a follow-up to our observations that estrogen may protect against memory change and Alzheimer's Disease in post-menopausal women. We have examined the effects of age and sex on brain structure measured by MRI for 116 BLSA participants. Cross-sectional results indicate smaller brain (gray and white matter) volumes in older compared with younger individuals and in women compared with men. Greater atrophy, indexed by increased ventricular size, was found in older compared with younger individuals and in men compared with women. Longitudinal analysis revealed that the ventricles increase in size by 1500 cubic mm over a one-year period. We have also examined the effects of age on several specific brain structures, such as the corpus callosum. Women were found to have a more bulbous splenium, posterior portion, of the corpus callosum than men, and the relative size of this region was smaller in older individuals. Furthermore, size of the splenium was positively correlated with neuropsychological performance in women, but there was no such relationship for men. This sex difference in brain- behavior associations is consistent with hypotheses of greater bilateral representation of function in women. Finally, we have continued our examination of the effects of steroid hormones on cognitive and brain function. A PET study revealed that women receiving estrogen replacement therapy differed from non-users in patterns of regional cerebral blood flow activation during memory task performance. Additional factors influencing brain changes in relation to age-associated memory change will be investigated as the longitudinal imaging study progresses.